Larock synthesis reaction

The Larock synthesis was used by Chen and coworkers to synthesize the 5-(triazolylmethyl)tryptamine MK-0462, a potent 5-HTid receptor agonist, as well as a metabolite [31, 32], The reaction was carried out on a 25-kg scale. Larock employed his methodology to prepare tetrahydroindoles [33], and Maassarani used this method for the synthesis of lV-(2-pyridyl)indoles [34]. The latter study features the isolation of cyclopaUadated lV-phenyl-2-pyridylamines. Rosso and coworkers have employed this method for the industrial scale synthesis of an antimigraine drug candidate 16. In this paper, removal of spent palladium was best effected by trimercaptotriazine (17), although many techniques were explored [35]. 

The Larock synthesis was used to synthesize Merck s rizatriptan (Maxalt, 5-(triazolylmethyl)tryptamine, MK-0462), a potent 5-HTid receptor agonist for the treatment of migraine. " The reaction was carried out on a 25 kg scale. 

Jana and Sinha have described the total synthesis of ibogaine, epiibo-gaine, and their analogs utilizing the Larock heteroannulation reaction for the creation of the suitably substituted indole (Scheme 25 2012T7155). 

Larock heteroannulation reaction was further extended and an intramolecular Larock indole synthesis of 2-chloroanilines bearing tethered acetylenes 106 was developed for the elaboration of a variety of polycyclic indole skeletons 107, for example, in 108-112. This intramolecular indolization method unveiled an unusual >sy -anidopalladation pathway of a tethered alkyne. The major side product is the dechlorinated starting material as a result of a reductive process. 

Ladenburg reaction, of pyridine 367 Larock synthesis (isoquinoline) 416 Lautens synthesis (indole) 141... 

D.C. Rogness, R.C. Larock, Synthesis of N-aryHsatins by the reaction of arynes with methyl 2-oxo-2-(arylamino)acetates, J. Org. Chem. 76 (2011) 4980-4986. 

A.V. Dubrovskiy, R.C. Larock, Synthesis of o-(diinethylainino)aryl ketones, acridones, acridinimn Salts, and IH-indazoles by the reaction of... 

Ring Closure Reactions Palladium(II) complexes (PdCl2L2, L=P, CN), covalently immobilized onto SBA-15 silica by a postsynthetic method, were used as catalysts in the Larock synthesis of indoles [86]. The reaction consisted of the heteroannulation of 2-iodoaniline and 2-bromoaniline with triethyl(phenylethynyl)silane showing high activities and selectivities to 3-phenyl-lH-indole 26 (Scheme 17). 

W. Kitching, Organomet. Chem. Rev. 3 61 (1968) R. C. Larock, Solvomercuration/Demercuration Reactions in Organic Synthesis, Springer-Verlag, New bik, 1986. 

Arylmetallic compounds have various, but not very widely used, applications in organic synthesis. Examples are acyl-de-metallation reactions using either dicobalt octacarbonyl in tetrahydrofuran (Seyferth and Spohn, 1969 Scheme 10-92), or carbon monoxide and a rhodium catalyst (Larock and Hershberger, 1980). 

Recently, Larock and coworkers used a domino Heck/Suzuki process for the synthesis of a multitude of tamoxifen analogues [48] (Scheme 6/1.20). In their approach, these authors used a three-component coupling reaction of readily available aryl iodides, internal alkynes and aryl boronic acids to give the expected tetrasubsti-tuted olefins in good yields. As an example, treatment of a mixture of phenyliodide, the alkyne 6/1-78 and phenylboronic acid with catalytic amounts of PdCl2(PhCN)2 gave 6/1-79 in 90% yield. In this process, substituted aryl iodides and heteroaromatic boronic acids may also be employed. It can be assumed that, after Pd°-cata-lyzed oxidative addition of the aryl iodide, a ds-carbopalladation of the internal alkyne takes place to form a vinylic palladium intermediate. This then reacts with the ate complex of the aryl boronic acid in a transmetalation, followed by a reductive elimination. 

Larock and coworkers identified a Pd-catalyzed double C-H-activation by reaction of N-(3-iodophenyl)anilines as 6/1-105 with alkynes as 6/1-106 [59]. Thus, reaction of 6/1-105 with 6/1-106 in the presence of Pd° led to 6/1-107 in reasonable yield. It can be assumed that the two palladacycles 6/1-108 and 6/1-109 act as intermediates. The procedure allows the efficient synthesis of substituted carbazoles (Scheme 6/1.28). 

The application of Heck cyclizations to the synthesis of indoles, indolines, and oxindoles was discovered independently by Mori-Ban s [296-298], and Heck s groups [299]. These investigators found that Pd can effect the cyclization of o-halo-lV-allylanilines to indoles under Heck conditions [300], The cyclization of o-halo-/V-allylanilines to indojes is a general and efficient methodology, especially with the Larock improvements where he cyclized o-halo-W-allylanilines and o-halo-N-acryloylanilides into indoles and oxindoles [301]. For example, the conversion of 279 to 280 can be performed at lower temperature, shorter reaction time, and with less catalyst to give 3-methylindole (280) in 97% yield. Larock s improved conditions, which have been widely adopted, are catalytic (2%) Pd(OAc)2, n-Bu4NCl, DMF, base (usually... 

Larock and co-workers described the one-step Pd-catalyzed reaction of o-haloanilines with internal alkynes to give indoles [385, 386]. This excellent reaction, which is shown for the synthesis of indoles 303, involves oxidative addition of the aryl halide (usually iodide) to Pd(0),. vyw-insertion of the alkyne into the ArPd bond, nitrogen displacement of the Pd in the resulting vinyl-Pd intermediate, and final reductive elimination of Pd(0). 

Similar Pd-catalyzed chemistry between o-iodoanilines and 1,3-dienes leading to 2-vinylindolines is also known, having been first described by Dieck and co-workers [398], This reaction, which is shown for the synthesis of 309, was discovered before Larock s work in this area. The same reaction with 1,3-cyclohexadiene gives the corresponding tetrahydrocarbazole in 70% yield. 

Prior to his work with internal alkynes, Larock found that o-thallated acetanilide undergoes Pd-catalyzed reactions with vinyl bromide and allyl chloride to give (V-acetylindole and N-acetyl-2-methylindole each in 45% yield [409]. In an extension to reactions of internal alkynes with imines of o-iodoaniline, Larock reported a concise synthesis of isoindolo[2,l-a]indoles 313 and 314 [410]. The regioselectivity was excellent with unsymmetrical alkynes. 

Unlike in the case of the preparation of indoles and benzofuranes, the synthesis of benzothiophenes from o-ethynyl-thiophenols is not known. A close analogy was reported by Larock, where phenylacetylene was coupled with 2-iodothioanisole. Ring closure of the formed o-ethynyl-sulfide was initiated by the addition of different electrophiles. The reaction led to the formation of the benzothiophene core bearing the electrophile in the... 

L1 I. ynd Zweitel Synthesis 1974, 658 Matsushita Negishi J. Am. Chem. Sue. 1981, 103, 2882. J. Chem Soc., Chem. Commun. 1982, 160. For similar reactions with other metals, see Larock Bernhardt Driggs J. Organomet. Chem. 1978, IS6, 45 Yoshida Tamao Takahashi-. Kannada Tetrahedron Lett. 1978, 2161 Brown Campbell J. Org. Chem. 1980, 45, 550 Baeckslrom Bjorkling Hdgberg Norin Acta Chem. Scand., Ser. B 1984, 38. 779. 

The classic ionic methods for the removal of an unwanted hydroxyl group are summarized in detail in the book by Larock [6]. One method involves—for primary and unhindered secondary alcohols—the synthesis of the corresponding mesylates or tosylates. These compounds are prepared readily and then transformed into the corresponding deoxy compounds by reduction [7], Alternatively, introduction of a thiolate or halogen by a nucleophilic reaction can also be used. These compounds can then be readily desulfurized or dehalogenated (Scheme 1). Tertiary alcohols present no problem either, because a... 

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